FDA and USDA announce key step to advance collaborative efforts to streamline produce safety requirements for farmers

Image result for FDA and USDA announce key step to advance collaborative efforts to streamline produce safety requirements for farmers
As part of the U.S. Food and Drug Administration and the U.S. Department of Agriculture’s ongoing effort to make the oversight of food safety stronger and more efficient, the FDA and the USDA today announced the alignment of the USDA Harmonized Good Agricultural Practices Audit Program (USDA H-GAP) with the requirements of the FDA Food Safety Modernization Act’s (FSMA’s) Produce Safety Rule.
The new step is part of an ongoing effort to streamline produce safety requirements for farmers. The joint announcement was made by Agriculture Secretary Sonny Perdue and FDA Commissioner Scott Gottlieb, M.D., during a visit by the Secretary to the FDA’s White Oak campus in Silver Spring, Md.

june 5, 2018

Image result for FDA and USDA announce key step to advance collaborative efforts to streamline produce safety requirements for farmers

 

Release

As part of the U.S. Food and Drug Administration and the U.S. Department of Agriculture’s ongoing effort to make the oversight of food safety stronger and more efficient, the FDA and the USDA today announced the alignment of the USDA Harmonized Good Agricultural Practices Audit Program (USDA H-GAP) with the requirements of the FDA Food Safety Modernization Act’s (FSMA’s) Produce Safety Rule.

The new step is part of an ongoing effort to streamline produce safety requirements for farmers. The joint announcement was made by Agriculture Secretary Sonny Perdue and FDA Commissioner Scott Gottlieb, M.D., during a visit by the Secretary to the FDA’s White Oak campus in Silver Spring, Md.

“Government should make things easier for our customers whenever possible and these important improvements help accomplish that goal,” said Secretary Perdue. “Specialty crop farmers who take advantage of a USDA Harmonized GAP audit now will have a much greater likelihood of passing a FSMA inspection as well. This means one stop at USDA helps producers meet federal regulatory requirements, deliver the safest food in the world and grow the market for American-grown food. This is an important first step. We look forward to continuing to work with FDA, other government agencies and especially our state partners to ensure proper training of auditors and inspectors, and to help producers understand changes in the audit.”

While the requirements of both programs are not identical, the relevant technical components in the FDA Produce Safety Rule are covered in the USDA H-GAP Audit Program. The aligned components include areas such as biological soil amendments; sprouts; domesticated and wild animals; worker training; health and hygiene; and equipment, tools and buildings. The alignment will help farmers by enabling them to assess their food safety practices as they prepare to comply with the Produce Safety Rule. However, the USDA audits are not a substitute for FDA or state regulatory inspections.

“We’re committed to working with USDA to pursue our shared goal of advancing food safety in a way that is efficient and helps farmers meet our regulatory standards. By working together, our two programs can advance these efforts more effectively,” said Commissioner Gottlieb. “Today’s announcement will help FDA and states better prioritize our inspectional activities by using USDA H-GAP audit information to prioritize inspectional resources and ultimately enhance our overall ability to protect public health. Inspections are key to helping to ensure that produce safety standards are being met, but they only provide a snapshot in time. Leveraging the data and work being done by USDA will provide us with more information so that we can develop a clearer understanding of the safety and vulnerabilities on produce farms as well as concentrate our oversight and resources where they are most needed.”

The Produce Safety Rule, which went into effect on Jan. 26, 2016, establishes science-based minimum standards for the safe growing, harvesting, packing and holding of fruits and vegetables grown for human consumption. The rule is part of the FDA’s ongoing efforts to implement FSMA. Large farming operations were required to comply with the rule in January 2018. However, the FDA had previously announced that inspections to assess compliance with the Produce Safety Rule for produce other than sprouts would not begin until Spring 2019. Small and very small farms have additional time to comply.

The USDA Harmonized GAP Audit Program is an audit developed as part of the Produce GAP Harmonization Initiative, an industry-driven effort to develop food safety GAP standards and audit checklists for pre-harvest and post-harvest operations. The Initiative is a collaborative effort on the part of growers, shippers, produce buyers, audit organizations and government agencies, including USDA. The USDA Harmonized GAP audit, in keeping with the Initiative’s goals, is applicable to all fresh produce commodities, all sizes of on-farm operations and all regions in the United States. For more information visit: https://www.ams.usda.gov.

Today’s announcement builds on a formal agreement signed earlier this year outlining plans to increase interagency coordination regarding produce safety, inspections of dual-jurisdiction facilities and biotechnology activities. The FDA and USDA are committed to continuing to work collaboratively to ensure that the requirements and expectations of the USDA H-GAP Audit Program remain aligned with the FDA’s Produce Safety Rule.

Farmers who are interested in learning more about this alignment and what they can do to prepare for compliance with the Produce Safety Rule can contact their regional representative of the Produce Safety Network or find more information at FDA.gov.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

The U.S. Department of Agriculture (USDA) is made up of 29 agencies and offices with nearly 100,000 employees who serve the American people at more than 4,500 locations across the country and abroad. We provide leadership on food, agriculture, natural resources, rural development, nutrition, and related issues based on public policy, the best available science, and effective management. We have a vision to provide economic opportunity through innovation, helping rural America to thrive; to promote agriculture production that better nourishes Americans while also helping feed others throughout the world; and to preserve our nation’s natural resources through conservation, restored forests, improved watersheds, and healthy private working lands.

Advertisements

Normal Operating Range (NOR) and Proven Acceptable Range (PAR)

str1

In June of this year, the EMA issued a revision of their earlier Q&A document focused on NORs, PARs, and DSp.(2) First issued in draft form in 2015, this has been revised based on feedback and consultation with industry. The document focuses on five questions, which are summarized below along with a reflection on the answer provided and its implications.

1. What is a Normal Operating Range (NOR) and how should NORs be presented in the marketing authorisation dossier?

Answer: NOR is not an established ICH term. The NOR describes a region around the target operating conditions that contain common operational variability (variability that can’t always be controlled). A NOR can be established for several process parameters of the same process step, with the understanding that the NOR does not represent deliberate adaptation of the process, and that the NOR does not cover a parameter range that affects the quality of the process output. Otherwise, a PAR or a multivariate Design space should be established. The use of NORs alone is not intended to introduce flexibility in the conditions for manufacturing but to better quantify the actual uncontrollable operational variability of process parameters. NORs should therefore be presented in marketing authorisations as what is practically achievable.

Requests to provide details of NORs have become an increasingly prevalent request from reviewers, predominantly in Europe, the absence of such information being classified as a deficiency. It was noted that the term NOR seemed to have risen to prominence even though this it is not an ICH term. Interestingly the answer draws specific attention to this and concedes this is not a formal ICH term. The framing of this question is interesting and already indicates the EMA thinking by posing the question—how should NORs be presented? the subsequent answer makes very clear NORs should be presented. Is this an issue? Arguably not as many organizations have presented NORs within section S2.2 without challenge. But it makes abundantly clear that this is unlikely to be optional.
So what is an NOR? The document provides the following definition:
An NOR describes a region around the target operating conditions that contain common operational variability (variability that cannot always be precisely controlled to a single and specific value). This is consistent with the thinking of many and should allow the definition of a range which reflects equipment capability. For example, a range of 35 °C ± 5 C° may reasonably be considered an NOR given the variability of the temperature control and calibration systems.
Overall while effectively introducing a “new” term this is an established concept already widely used and thus this is not considered as a significant concern.
Image result for Proven Acceptable Range

What Is a Proven Acceptable Range (PAR) and How Should PARs Be Justified and Presented in the Marketing Authorization Dossier?


Again a specific definition is provided:
The PAR is defined as a characterized range of a process parameter for which operation within this range, while keeping other parameters within set points or NORs, will result in producing a material meeting relevant quality criteria (ICH Q8 R2).(1)
A key phrase within this seems to be the statement that other parameters must be kept constant. Is this ever the reality, and what is constant? Later in the document in the answer pertaining to DSp, there is effective recognition that some form of interrelationship will generally exist. What is perhaps more important is establishing the criticality of this relationship not that one simply exists. Later within the answer it is also stated that where an interaction exists between different parameters, the parameters should be included in a Design Space. One might be forgiven for believing that this may penalize the more diligent applicant who seeks to properly study possible interactions. Missing at present is clarity around what happens if you explore multiple parameters and find no interactions or more likely no “significant” interactions. In such circumstances where the interactions have no impact, it should be possible to justify multiple ranges (or at least a range wider than the NOR).
There is also a need to understand more about when an interaction is significant. If there are no interactions across the ranges proposed and no impact on drug substance quality is demonstrated with multivariate experiments, then surely we do not need a design space—it adds no value and makes no sense.
ref 1
2 Questions and answers: Improving the understanding of NORs, PARs, DSp and normal variability of process parameters, EMA/CHMP/CVMP/QWP/354895/2017.
///////////////Normal Operating Range, NOR, Proven Acceptable Range, PAR, ich, maa

A review of fungal contamination in pharmaceutical products and phenotypic identification of contaminants by conventional methods

str1
Article (PDF Available)inEuropean Journal of Parenteral and Pharmaceutical Sciences 17(1):4-19 · January 2011
Abstract
Microbial contamination of pharmaceutical products is one of the major reasons for product recall and manufacturing problems. Knowledge of the distribution of survival microorganisms in pharmaceutical environments is critical in the process control of non sterile and sterile pharmaceutical products. This knowledge is somewhat limited by the ubiquitous distribution of microorganisms in manufacturing facilities particularly fungal distribution. Identification of these fungi isolates from pharmaceutical environments using standard identification procedures requires experienced skilled technologists. To develop the proper corrective action when out of specification results are obtained, accurate fungal identification is needed if the contamination source has to be determined and tracked. Corrective action may not be effective if erroneous information is used to solve a given problem. This review provides guidance about knowledge of fungal contamination in pharmaceutical products and outlines an economic approach to phenotypic identification using conventional methods.

A review of fungal contamination in pharmaceutical products and phenotypic identification of contaminants by conventional methods (PDF Download Available). Available from: https://www.researchgate.net/publication/275335972_A_review_of_fungal_contamination_in_pharmaceutical_products_and_phenotypic_identification_of_contaminants_by_conventional_methods [accessed Jun 12, 2017].

https://www.researchgate.net/publication/275335972_A_review_of_fungal_contamination_in_pharmaceutical_products_and_phenotypic_identification_of_contaminants_by_conventional_methods

REFERENCES

http://shodhganga.inflibnet.ac.in/bitstream/10603/40641/5/chapter%202.pdf

Any pharmaceutical product, whether manufactured in the hospital or industrial environment, has the potential to be contaminated with microorganisms. With sterile products, any microbial contamination presents an unacceptable risk; with non-sterile products, the implication of the contamination is dependent upon whether the microorganism can be considered ‘objectionable’, and then to the extent that it can cause patient harm (and here a risk assessment is ordinarily required)1.

There are different types of microorganisms associated with product recalls. At this stage into the 21st century, fungal contamination of nonsterile products is one of the major reasons for product recalls, production shutdowns, and losses in labour and manufacturing. This can result in a reduced shelf life by compromising product integrity or present potential health hazard to patients2. Many of the reasons are due to the lack of quality control, process control and proper testing.

Most reports relating to the contamination of pharmaceutical products centre on bacterial contamination rather than fungi. The reasons for this may relate to few ‘microbiology’ laboratories in pharmaceutical organisations having trained mycologists; to an underestimation of the association between fungi and product contamination incidents; and due to a lack of appreciation of the risks that fungi can pose to cleanrooms and controlled environments3. This article considers some of these issues and, in doing so, argues that the contamination risk posed by fungi to pharmaceutical products is greater than the level of industrial and academic interest would suggest.

Fungal contamination risks

Fungi are more evolutionarily advanced forms of microorganisms, as compared to the prokaryotes (such as bacteria). Fungi are commonly divided into two distinct morphological forms: yeasts and hyphae (or filamentous). Yeasts are unicellular fungi which reproduce asexually by blastoconidia formation (budding) or fission4. Fungal contamination in pharmaceutical products represents a potential hazard for two reasons. First, it may cause product spoilage; the metabolic versatility of fungi is such that any formulation ingredient from simple sugars to complex aromatic molecules may undergo chemical modification in the presence of a suitable organism. Spoilage will not only affect therapeutic properties of the product but may also discourage the patient from taking the medication. Second, product contamination represents a health hazard to the patient, although the extent of the hazard will vary from product to product and patient to patient, depending on the types and numbers of organisms present, the route of administration, and the resistance of the patient to infection. https://www.europeanpharmaceuticalreview.com/24118/topics/microbiology-rmm/fungal-contamination-pharmaceutical-products-growing-menace/

Image result for fungal contamination in pharmaceutical products

Image result for fungal contamination in pharmaceutical products

Image result for fungal contamination in pharmaceutical products

Image result for fungal contamination in pharmaceutical products

Tim Sandle

Microbiology, Biotechnology

PhD
Vijayakumar Rajendran

Vijayakumar Rajendran

Immunology, Biotechnology, Mycology

Ph.D

Generics: FDA´s New Guidance on Prior Approval Supplements

Image result for Prior Approval Supplements

Generics: The US Food and Drug Administration (FDA) recently published a new Guidance regarding Prior Approval Supplements (PAS). Read more about FDA´s Guidance for Industry “ANDA Submissions – Prior Approval Supplements Under GDUFA“.

http://www.gmp-compliance.org/enews_05634_Generics-FDA%B4s-New-Guidance-on-Prior-Approval-Supplements_15721,Z-RAM_n.html

On October 14, 2016, the US Food and Drug Administration (FDA) published a new Guidance regarding Prior Approval Supplements (PAS).
FDA says that “this guidance is intended to assist applicants preparing to submit to FDA prior approval supplements (PASs) and amendments to PASs for abbreviated new drug applications (ANDAs)”.

Specifically, the guidance describes how the Generic Drug User Fee Amendments of 2012 (GDUFA) performance metric goals apply to:

  • A PAS subject to the refuse-to-receive (RTR) standards;
  • A PAS that requires an inspection;
  • A PAS for which an inspection is not required;
  • An amendment to a PAS;
  • Other PAS-related matters.

GDUFA is designed to speed the delivery of safe and effective generic drugs to the public and reduce costs to industry. That requires that FDA and human generic drug manufacturers meet certain requirements and commitments. “FDA committed to review and act on a certain percentage of PASs within a specified period from the date of submission for receipts in fiscal year (FY) 2015 through FY 2017. The percentage of PASs that FDA has committed to review and act on increases with each fiscal year; the deadlines for review also depend on whether consideration of a PAS requires an inspection.”

Changes to an approved application:
The criteria laid down in FDA regulations for submitting information as a PAS (major change), as a Changes Being Effected-Supplement (CBE-supplement, moderate change), or in an annual report (minor change) were not changed by GDUFA.

Timelines depending on inspections for PAS submissions:
The GDUFA goal date for a PAS depends on whether the PAS requires an inspection. If a PAS does not require an inspection, the goal date is 6 months from the date of submission; but if a PAS requires an inspection, the goal date is 10 months from the date of submission. An initial goal date of 6 months occasionally may change to a 10-month goal date if, during the review, FDA determines an inspection is necessary. If an amendment is made to a PAS, the GDUFA goal date associated with that PAS may be revised. FDA strongly recommends that, at the time of submission, a supplement should be complete and ready for a comprehensive review.

Submission of Supplements:
The following information should be provided on the first page of the PAS:

  • A statement indicating whether the PAS is for a new-strength product;
  • A statement indicating whether the submission is an amendment to a PAS, and if so the corresponding tier classification;
  • A statement indicating whether the PAS contains any manufacturing or facilities changes;
  • A list of the specific review disciplines to review the PAS (Chemistry, Labeling, DMF, Bioequivalence, Microbiology, or Clinical);
  • If expedited review is requested, the label Expedited Review Request should be placed prominently at the top of the submission. The submission should include a basis for the expedited review request.

It is possible to submit multiple PASs for the same chenge as “grouped supplements”. These are submitted to ANDAs by a single applicant for the same chemistry, manufacturing, and controls (CMC) change to each application. Because the grouped supplements are being reviewed together, generally they will have the same GDUFA goal date. Although the submissions are considered a group, each supplement in the group is considered its own individual submission and therefore would require a GDUFA PAS fee for each ANDA identified in the group.

Alternative Submissions:

  • Identify a lead ANDA for a group of PASs (only one fee is paid, or fewer than all the fees for the group are paid);
  • For some changes (e.g., widening of an approved specification or introduction of a new API supplier) once a PAS is submitted and approved, subsequent supplements for the same change to other ANDAs may be classified as CBE-30s;
  • comparability protocol submitted in a PAS to an ANDA for a specific drug product, once approved, may justify a reduced reporting category for the same change in subsequent supplements to that ANDA.

If FDA finds that a supplement submitted as a CBE supplement should have been submitted as a PAS, it will notify the applicant. The applicant is not required to withdraw the CBE supplement because when FDA sends a letter explaining that the applicant’s submission is not accepted as a CBE supplement, FDA administratively closes the CBE supplement, and it is considered withdrawn. The applicant may resubmit the supplement as a PAS for FDA approval before distribution of the drug product, along with the required GDUFA user fee. The GDUFA performance metric goals and applicable user fees will apply to that PAS and the GDUFA review clock will start from the date of submission of that PAS.

For more information please see the FDA Guidance for industry “ANDA Submissions – Prior Approval Supplements Under GDUFA“.

///////////Generics, FDA,  New Guidance,  Prior Approval Supplements

ENHANCED ANALYTICAL METHOD CONTROL STRATEGY CONCEPT

Image result for ANALYTICAL METHOD CONTROL STRATEGY

ENHANCED ANALYTICAL METHOD CONTROL STRATEGY CONCEPT

The benefits of quality by design (QbD) concepts related to both product (ICH Q8)1 and drug substance (ICH Q11)2 are well-established, particularly in regards to the potential to use knowledge to affect process changes without major regulatory hurdles, i.e., revalidation/regulatory filing, etc. Less wellestablished, but potentially of significant value, is the application of the same concepts to analytical methods.

Analytical methods play an obvious key role in establishing the quality of final product as they establish conformance with product acceptance criteria (i.e., specifications) and indicate the integrity of the product through indication of product stability. Analytical methods are validated, like manufacturing processes, but what if the operational ranges could be established during method validation when demonstrating fitness for purpose?

Would it be possible to drive method improvement, especially post validation in the same way that the concept of continuous improvement is a key driver for manufacturing processes? Despite this attractive “value proposition”, there is to date little evidence that as an industry this is being practically realized.

The result is that many methods used in a QC environment lag well behind technical developments in the analytical field, often leading to the use of suboptimal procedures that impact adversely on the efficiency within the laboratory. The challenge is to create an environment whereby such changes can be made efficiently and effectively.

One approach is to apply the principles of ICH Q8−10; delivering a science and risk based approach to the development and validation of analytical methods, establishing a method operable design region (MODR) within which changes can be made. Such a framework is illustrated in Figure 1.

 

str0

This starts with a definition of the effective requirements of the method, an analytical target profile (ATP), this taking the specific form of acceptance criteria for method performance. Such a process can be used to not only establish effective analytical methods but is also supportive of continual improvement, specifically within the MODR. However, such a concept is potentially limited in that the expectation is that changes are restricted to within the MODR.

Such restrictions may inhibit continuous improvement. A prime example is change of stationary phase or a change from HPLC to UPLC; both fall outside of the original MODR. Historically such changes have been notoriously difficult and often therefore avoided unless imperative. A recent publication13 examined this, presenting a method enhancement concept that would allow minor changes outside of the MODR. This is based on the realization that performance of any analytical method is based on the conduct of a system suitability test (SST); such tests ensure the method’s fitness for purpose.

Karlsson et al. stated that changes outside of the initial MODR may be possible provided that the method principle is unchanged, failure modes are the same, and the SST is capable of detecting these, both for the original method and for any method changes that fall outside of the original MODR. Put simplychanges can be made provided the SST criteria are passed. A change from HPLC to UPLC was used to illustrate this. Revalidation of the method is still required, but critically such changes do not require regulatory interaction but can be managed through internal quality systems.

1 ICH Q8 Pharmaceutical Development. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_
R1/Step4/Q8_R2_Guideline.pdf.
(2) ICH Q11 – Development and Manufacture of Drug Substances
(Chemical Entities and Biotechnological/Biological Entities) Q11.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Step_4.pdf (Aug 2009).

 

////////ENHANCED,  ANALYTICAL METHOD CONTROL , STRATEGY CONCEPT

 

Drug Approval Strategies in the Age of Fast Track, Breakthrough Therapy and Accelerated Approval

Image result for Process Validation

Process Validation and Regulatory Review

Drug Approval Strategies in the Age of Fast Track, Breakthrough Therapy and Accelerated Approval

To meaningfully discuss the process validation and regulatory approval strategies required for drugs that have been designated Fast Track, Breakthrough Therapy or Accelerated Approval drugs, we must first clarify these designations and briefly remind ourselves what the Process Validation guidance looks like. Then we will be able to clearly identify challenges and approaches to these barriers when working to bring a Fast Track, Accelerated Approval or Breakthrough Therapy drug to market.

Fast Track designation – Fast Track drugs treat serious conditions where there is an unmet medical need. Concluding that a condition is serious and that there is an unmet medical need most definitely leaves room for judgement, but generally speaking, the conditions these drugs treat are life-threatening, and the drug in question is expected to contribute to survival, daily functioning or the likelihood that a condition will advance to a very serious state. Fast Track drugs receive the benefit of more frequent meetings and communication with the FDA, and the drug qualifies for Accelerated Approval and rolling review of the Biologic License Application (BLA) or New Drug Application (NDA).

Breakthrough Therapy – Breakthrough Therapy status can be assigned to drugs that treat a serious condition when preliminary clinical data show significantly improved outcomes compared to treatments currently on the market. Breakthrough Therapies are eligible for: Fast Track designation benefits, extensive FDA guidance on effective drug development early in the development process and organizational commitment, including access to FDA senior managers.

Accelerated Approval – The FDA established accelerated approval regulations in 1992. Accelerated Approval could be given to drugs that met a serious unmet medical need, and approval was based on a surrogate endpoint. Fast forward to 2012 when Congress passed the Food and Drug Administration Safety Innovations Act (FDASIA). This amendment to the Federal Food, Drug, and Cosmetic Act (FD&C Act) allowed approval to be based on either a surrogate endpoint per the 1992 regulations or approval based on an intermediate clinical endpoint. For example, as a result of the 2012 legislation, a cancer drug could be approved based on the surrogate endpoint of increasing the probability of cancer to going into remission or the intermediate clinical endpoint of shrinking tumor size—an outcome that is strongly correlated with the ability to much more successfully treat cancer and induce remission.

These FDA designations are clearly designed to increase the availability and speed to market of drugs treating serious conditions where unmet medical needs exist. Given that nimbleness and speed has historically not been the pharmaceutical industry’s nor FDA’s strong suit—commercialization of a drug has historically taken on average 12 years and cost up to $2.5B (including expenditure outlays and opportunity costs). The ability for these designations to save both time and money is very attractive. However, given the slow-moving nature of the industry, changes in both mindset and approaches are needed by both drug innovators and regulators to validate processes and ensure drug quality within the faster-moving constructs.

Let’s now turn to the most recent Process Validation guidance so that we may juxtapose that system with the nimble needs of Fast Track Designation, Breakthrough Therapy and Accelerated Approval drugs—ultimately, making some observations regarding needed Process Validation and overall regulatory approval approaches as the industry moves towards accelerated development processes for an increasing number of drugs.

Image result for Process Validation

WHAT IS PROCESS VALIDATION?
According to the FDA’s 2011 Process Validation (PV) guidance, “For purposes of this guidance, process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the lifecycle of the product and process.”

The Three Stages of Process Validation:
Stage 1: Process Design–manufacturing process is defined during this stage and is based on knowledge acquired through development and scale-up activities.

Stage 2: Process Qualification–process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.

Stage 3: Continued Process Verification–ongoing assurance during manufacturing that the process is controlled and the outcome predictable.

Image result for Process Validation

Keys for Successful Validation Include:
• Gaining knowledge from the product and process development
• Understanding sources of variation in the production process
• Determining the presence of and degree of variation
• Understanding the impact of variation on the process and end product
• Controlling variation in a manner aligned with Critical Quality Attributes (CQA) and the risk a given attribute introduces to the process

Process Qualification, a key component of Process Validation, should be based on overall level of product and process understanding, level of demonstrable control, data from lab, pilot and commercial batches, effect of scale and previous experience with similar products and processes. Process Qualification is generally recommended to be based on higher levels of sampling, additional testing and greater scrutiny of process performance than would be typical of routine commercial production.

As we will now explore, some of the demands of Process Qualification and overall Process Validation is severely challenged by the approaches required when bringing a Fast Track, Accelerated Approval or Breakthrough Therapy drug to market.

Image result for Process Validation

NOVEL APPROACHES NEEDED FOR ACCELERATED APPROVALS
Historically, it has taken an average of 12 years and, according to a Tufts Center for the Study of Drug Development (CSDD) report, including expenditures and opportunity costs, an average of ~$2.6 billion to bring a prescription drug to market. This paper will refrain from making editorial comments about this pharmaceutical industry fact; however, the undeniable reality is that the speed required at every point in the industry to develop Fast Track, Accelerated Approval or Breakthrough drugs is having a profound impact.

Image result for Process Validation

Approval of a Breakthrough drug, which of course is classified for Accelerated Approval, means manufacturers need to develop Chemistry, Manufacturing and Controls (CMC) data in about half the time of the traditional process. In addition, Breakthrough designation does not mean the innovator company can do less. In order to meet these accelerated timelines, they do need to start analytical methods creation and product and process characterization sooner, and handle the process differently. Validation of a process traditionally has called for sufficient data and an adequate number of runs to convince the manufacturer (and regulators) that the process works. As we will explore below, Breakthrough therapies are often in the market before the product is fully validated.

However, the guiding force behind these new approaches is that despite sharply reduced timeframes, manufacturers cannot compromise patient safety or product supply. Therefore, characterization of critical product and process attributes is typically required much earlier in the process.

Image result for Process Validation

Challenges and Realities of Process Validation and Regulatory Approval within the Accelerated Drug Paradigm:
• The collaboration and communication required between the FDA and innovator companies is extensive. Given limited FDA resources and extensive resources required by the organizations of innovator companies, is the growth of the Fast Track/Breakthrough Therapy/Accelerated Approval programs sustainable?
• New Drug Applications (NDA) for Breakthrough Therapies include less manufacturing information and data requiring alternative risk-mitigation approaches and often nontraditional statistical models.
• Both patient safety and product supply is at the forefront, without the data and historical knowledge traditionally used to address these concerns.
• The primary concerns for CMC reviewers include incomplete characterization of the drug, underdeveloped analytical methods and a lack of full understanding of a product’s Critical Quality Attributes (CQA) and associated risks.
• Process Validation will, in many cases, be incomplete at product launch.

Image result for Process Validation

THE CHANGED PARADIGM RESTORED TO ORDER (SORT OF)
The “restored order” for the approval of, and ultimate Process Validation for, Breakthrough/Accelerated Approval drugs will not look like anything we normally see. Again, all Breakthrough and Accelerated Approval drugs address very serious conditions and offer treatment where none currently exists, or offers benefits well above and beyond drug products currently on the market. Therefore, flexibility has been applied to segments of the traditional product review and approval process to speed the availability of treatments for these critical conditions.

Despite the flexibility in, and often changes to the product review and approval process, patient safety remains at the forefront, as well as the guarantee of consistent product supply.

Approaches for Successfully Handling the Approval and Validation of Accelerated Approval Drugs:
• Open and transparent communication with the FDA is essential throughout the entire approval and post-market process. The pharmaceutical company mindset of not wanting to learn certain information for fear of needing to revalidate based on those discoveries has no place in this new reality. New information will be learned pre- and post-launch, and plenty of amendments will need to be filed.
• Given the compressed development timeframes, less stability data will be available at submission. Additional data will be submitted via amendments during the review cycle, and in some cases, post-market.
• Launch commercial process with limited experience and optimize post-approval–the classic three runs is not the guiding force within this construct. The level of flexibility regulators will extend is determined for each specific product. Factors taken into consideration include: riskiness of product characteristics, seriousness of the condition and medical need, complexity of manufacturing processes, state of the innovator’s quality system and merits of the innovator’s risk-based quality assessment including Critical Quality Attributes (CQA).
• Novel statistical models and approaches will need to be applied in many cases. Representative samples and assays for these models will likely need to be acquired from sources, like prior knowledge and use of comparability protocols. Also, determination of the appropriate use of stability data from representative pilot scale lots will be required.
• Manufacturers should freely acknowledge where data is limited, demonstrate that the missing data pose no risk to patient safety or product supply and outline post-market strategy for acquiring the missing data. Conversations with the FDA are clearly required for successful outcomes.
• Focus on patient safety and reliable supply of quality product at launch, not process optimization. In addition, begin critical product attributes and process characterization work much earlier than a typical pharmaceutical development process. In many cases, consider broader product quality ranges for non-Critical Quality Attributes until further manufacturing experience is acquired post-approval.

Image result for Process Validation

Enhance analytical methods and understanding to offset more limited process understanding and to support future comparability work. Extremely important, involve commercial Quality Control representatives in the development assay design.
• Again, CMC activities that may be incomplete at launch include: Process Validation, stability studies on commercial product, manufacturing scale/tech transfer data and complete control system data.
• A post-approval product lifecycle management plan is a must, and it needs to be included in the filing to support deferred CMC activities.

Fast Track, Breakthrough Therapy and Accelerated Approval drugs have profoundly changed the thinking and approach to Process Validation and other CMC activities.

Image result for Process Validation

Sources:
Joseph A. DiMasia, Henry G. Grabowskib, Ronald W. Hansenc, “Innovation in the Pharmaceutical Industry: New Estimates of R&D costs,” Tufts Center for the Study of Drug Development, Tufts UniversityJ. Wechsler, “Breakthrough Drugs Raise Development and Production Challenges,” Pharmaceutical Technology 39 (7) 2015.Earl S. Dye, PhD, “CMC/GMP Considerations for Accelerated Development and Launch of Breakthrough Therapy Products,” Roche“Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics,” U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), May 2014 ProceduralAnthony Mire-Sluis, Michelle Frazier, Kimberly May, Emanuela Lacana, Nancy Green, Earl Dye, Stephan Krause, Emily Shacter, Ilona Reischl, Rohini Deshpande and Joe Kutza, “Accelerated Product Development: Leveraging Industry and Regulator Knowledge to Bring Products to Patients Quickly,” BioProcess International, December 2014

Daniel Alsmeyer and Ajay Pazhayattil, Apotex Inc., “A Case for Stage 3 Continued Process Verification,” Pharmaceutical Manufacturing, May 2014

Image result for Process Validation

Image result for Process Validation

Image result for Process Validation

/////////////Process Validation, Regulatory Review, Drug Approval Strategies,  Fast Track, Breakthrough Therapy, Accelerated Approval